Phar 15.34(6) (6) If administration of the compounded sterile preparation has not begun within 4 hours following the start of preparation, it shall be promptly, properly, and safely discarded.

Phar 15.34 History History: CR 16-085: cr. Register April 2018 No. 748 eff. 11-1-18; CR 22-007: r. and recr. Register July 2022 No. 799, eff. 8-1-22.

Phar 15.35 Phar 15.35 Sterilization methods.

Phar 15.35(1) (1) Sterilization methods employed shall sterilize while maintaining its physical and chemical stability and the packaging integrity of the compounding sterile preparations. The efficacy of sterilization and depyrogenation of container closure systems performed in the pharmacy shall be established, documented, and reproducible.

Phar 15.35(2) (2) Pre-sterilization requirements shall meet all of the following:

Phar 15.35(2)(a) (a) During all compounding activities that precede terminal sterilization, including weighing and mixing, compounding personnel shall be garbed and gloved in the same manner as when performing compounding in an ISO Class 5 environment. All pre-sterilization procedures shall be completed in an ISO Class 8 or better environment.

Phar 15.35(2)(b) (b) Immediately before use, all nonsterile measuring, mixing, and purifying devices used in the compounding process shall be thoroughly rinsed with sterile, pyrogen-free water and then thoroughly drained or dried.

Phar 15.35(3) (3) Sterilization shall be performed utilizing one of the following methods:

Phar 15.35(3)(a) (a) Sterilization by filtration. Sterilization by filtration involves the passage of a fluid or solution through a sterilizing grade membrane to produce a sterile effluent. Filtration may not be used when compounding a suspension when the suspended particles are removed by the filter being used. This method shall meet all of the following:

Phar 15.35(3)(a)1. 1. Sterile filters used to sterile filter preparations shall meet all of the following requirements:

Phar 15.35(3)(a)1.a. a. Be pyrogen-free and have a nominal pore size of 0.22 microns.

Phar 15.35(3)(a)1.b. b. Be certified by the manufacturer to retain at least 107 microorganisms of a strain of Brevundimonas diminuta per square centimeter of upstream filter surface area under conditions similar to those in which the compounded sterile preparations will be filtered.

Phar 15.35(3)(a)1.c. c. Be chemically and physically stable at the compounding pressure and temperature conditions.

Phar 15.35(3)(a)1.d. d. Have sufficient capacity to filter the required volumes.

Phar 15.35(3)(a)1.e. e. Yield a sterile filtrate while maintaining pre-filtration pharmaceutical quality, including strength of ingredients of the specific compounded sterile preparations.

Phar 15.35(3)(a)2. 2. The filter dimensions and liquid material to be sterile filtered shall permit the sterilization process to be completed rapidly without the replacement of the filter during the filtering process.

Phar 15.35(3)(a)3. 3. When compounded sterile preparations are known to contain excessive particulate matter, one of the following shall occur:

Phar 15.35(3)(a)3.a. a. A pre-filtration step using a filter of larger nominal pore size.

Phar 15.35(3)(a)3.b. b. A separate filter of larger nominal pore size placed upstream of the sterilizing filter to remove gross particulate contaminants before the compounding sterile compound is passed through the sterilizing grade filter.

Phar 15.35(3)(a)4. 4. Sterilization by filtration shall be performed entirely within an ISO Class 5 or better air quality environment.

Phar 15.35(3)(a)5. 5. Filter units used to sterilize compounded sterile preparations shall be subjected to the manufacturers’ recommended post-use integrity test.

Phar 15.35(3)(b) (b) Sterilization by steam heat. The process of thermal sterilization using saturated steam under pressure shall be the method for terminal sterilization of aqueous preparations in their final, sealed container closure system. The effectiveness of steam sterilization shall be established and verified with each sterilization run or load by using biological indicators, physicochemical indicators and integrators. This method shall meet all of the following:

Phar 15.35(3)(b)1. 1. All materials shall be directly exposed to steam under adequate pressure for the length of time necessary, as determined by use of appropriate biological indicators, to render the items sterile. The duration of the exposure period shall include sufficient time for the compounded sterile preparation to reach the sterilizing temperature.

Phar 15.35(3)(b)2. 2. The compounded sterile preparation and other items shall remain at the sterilizing temperature for the duration of the sterilization period. The sterilization cycle shall be designed to achieve a sterility assurance level of 10-6.

Phar 15.35(3)(b)3. 3. Compounded sterile preparations shall be placed in trays which allow steam to reach the compounded sterile preparations without entrapment of air. Paper, glass, and metal devices or items shall be wrapped in low lint protective fabric, paper, or sealed in envelopes that will permit steam penetration and prevent post sterilization microbial contamination.

Phar 15.35(3)(b)4. 4. Immediately before filling ampules and vials, solutions shall be passed through a filter having a nominal pore size of not larger than 1.2 microns for removal of particulate matter.

Phar 15.35(3)(b)5. 5. Sealed containers shall be able to generate steam internally. Stoppered and crimped empty vials shall contain a small amount of moisture to generate steam. Deep containers, including beakers and graduated cylinders, shall be placed on their sides to prevent air entrapment or have a small amount of water placed in them.

Phar 15.35(3)(b)6. 6. Porous materials and items with occluded pathways shall only be sterilized by steam if the autoclave chamber has cycles for dry goods.

Phar 15.35(3)(b)7. 7. The steam supplied shall be free of contaminants and generated using clean water.